Functional Ingredients Associated with the Prevention and Suppression of Locomotive Syndrome: A Review

Abstract

In 2007, the Japanese Orthopaedic Association proposed the concept of locomotive syndrome, a comprehensive description of conditions involving the functional decline of the locomotor system. Locomotive syndrome includes bone-related diseases such as osteoporosis, joint cartilage and disc-related diseases such as osteoarthritis and lumbar spondylosis, and sarcopenia and locomotive syndrome-related diseases. If left untreated, these diseases are likely to reduce mobility, necessitating nursing care. To prevent the progression of locomotive syndrome, a daily exercise routine and well-balanced diet are important, in addition to recognizing one’s own decline in mobility. Therefore, research on the effectiveness of functional ingredients in the prevention and suppression of locomotive syndrome progression is ongoing. In this review, we summarize the latest reports on the effectiveness of five functional ingredients, namely, epigallocatechin gallate, resveratrol, curcumin, ellagic acid, and carnosic acid, in the treatment of osteoarthritis, osteoporosis, and rheumatoid arthritis, which are considered representative diseases of the locomotive syndrome.

1. INTRODUCTION

Locomotive syndrome, a novel concept proposed by the Japanese Orthopaedic Association in 2007, is a comprehensive description of conditions involving the functional decline of the locomotor system. Individuals with locomotive syndrome are at high risk of requiring nursing care due to functional declines.¹⁾ Locomotive syndrome is caused by diseases of the locomotor system itself or locomotor insufficiency due to aging.¹⁾ Diseases of the locomotor system include osteoarthritis, osteoporosis, rheumatoid arthritis, dorsal column stenosis, fractures, paralysis of the limbs and trunk, back pain, and stiff shoulders. The age-related functional declines of the locomotor system include muscle weakness in the limbs and trunk, loss of strength and general endurance, limited joint mobility due to muscle shortening and muscle atrophy, and joint and muscle pain. Bone-related diseases such as osteoporosis and osteoporosis-related diseases,²⁾ diseases related to articular cartilage and intervertebral discs such as osteoarthritis and lumbar spondylosis,³⁾ and diseases related to sarcopenia and locomotive syndrome are seldom directly life-threatening⁴⁾; however, if allowed to progress, patients are likely to develop decreased mobility or become bedridden, necessitating nursing care.⁵⁾ Furthermore, locomotive syndrome is associated with cardiovascular disorders.⁶⁾ The number of patients with locomotive syndrome has rapidly increased in recent years, and the prevention and control of its progression are significant issues that need to be addressed.⁷⁾ It is crucial to recognize the decline in one’s own locomotor function and start an exercise regime as early as possible to prevent the progression of locomotive syndrome. The main targets of treatment for locomotive syndrome are three chronic diseases: osteoporosis, osteoarthritis of the knee, and osteoarthritis of the spine. In addition to these, spinal compression fractures and rheumatoid arthritis are important considerations. If left untreated, these patients often suffer pain and numbness, as well as increased susceptibility to fractures. In addition, risk factors other than aging have been reported in patients with locomotive syndrome caused by rheumatoid arthritis,⁸⁾ and prevention is important. Daily exercise routines and a well-balanced diet are believed to be imperative for preventing locomotive syndrome. Glucosamine and other dietary components have been reported to be effective in several musculoskeletal diseases,⁹⁾ such as suppressing bone loss in ovariectomized mice.¹⁰⁾ In addition, the preventative role of calcium in osteoporosis is widely known.¹¹⁾ Therefore, studies are being conducted on the effectiveness of functional food ingredients in the prevention and suppression of locomotive syndrome progression.

In this review, we summarize the latest reports on the use of five functional ingredients, namely, epigallocatechin gallate (EGCG), trans-1,2-(3,4′,5-trihydroxydiphenyl) ethylene (resveratrol), curcumin, ellagic acid, and carnosic acid, in the treatment of osteoarthritis, osteoporosis, and rheumatoid arthritis. The chemical structures of these functional components are shown in Fig. 1.

Fig. 1. Chemical Structures of Five Food-Derived Components

(a) Epigallocatechin gallate (EGCG), (b) resveratrol, (c) curcumin, (d) ellagic acid, and (e) carnosic acid.

2. OSTEOARTHRITIS

Osteoarthritis is a painful condition in which the cartilage in the joints degrades owing to aging or muscle loss.¹²⁾ As the cartilage wears down, the space between the bones of the joint narrows, exposing the inner bone and causing spike-like protrusions to form at the edges of the bone, leading to bone deformity.¹³⁾ Pathologic changes in osteoarthritic joints include varying degrees of synovial inflammation, ligamentous degeneration, meniscal tears, and hypertrophy of the joint capsule, in addition to articular cartilage deterioration, subchondral bone thickening, and osteophyte formation.¹³⁾

The treatment of osteoarthritis includes painkillers and topical medications for mild symptoms and hyaluronic acid injections into the joint.¹⁴⁾ In addition, musculoskeletal rehabilitation¹⁵⁾ (i.e., quadriceps strength training¹⁶⁾), joint range-of-motion training,¹⁷⁾ and physical therapy¹⁸⁾ (i.e., heat therapy¹⁹⁾), are performed. However, if these treatments are not curative, patients often must undergo surgery for artificial joint replacement.¹⁴⁾ Although the literature on the use of functional food ingredients in the treatment of osteoarthritis is limited, several reports have been published.^20–22) In this section, we discuss and present the results of studies pertaining to the use of five typical functional ingredients, namely, EGCG, resveratrol, curcumin, ellagic acid, and carnosic acid, in the treatment of osteoarthritis. Glucosamine proteoglycan and chondroitin are used to control the progression of osteoarthritis symptoms and are widely known to affect the degradation and synthesis of type II collagen. However, the ingredients discussed in this review may be involved via other mechanisms. A schematic representation of the prevention of osteoarthritis using functional ingredients is shown in Fig. 2. In this chapter, we summarize the effects of these five components on the prevention of osteoarthritis through their effects on inflammation, matrix degradation, autophagy, apoptosis, and oxidative stress.

Fig. 2. Mechanism of Action of Functional Ingredients in the Prevention of Osteoarthritis

A: epigallocatechin gallate (EGCG); B: resveratrol; C: curcumin; D: ellagic acid; E: carnosic acid. Blue indicates inhibition. Red arrows indicate upregulation. Nuclear factor-kappa-B (NF-κB), sirtuin (SIRT), forkhead box O (FOXO), interleukin (IL), tumor necrosis factor (TNF), cyclooxygenase (COX), inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), hypoxia-inducible factor (HIF), phosphoinositide 3-kinase (PI3k), Ak strain transforming (AKT), light-chain-3 (LC3), Bcl-2-associated X protein (Bax), B-cell/CLL lymphoma 2 (Bcl-2), NF-E2-related factor 2 (NRF2), heme oxygenase 1 (HO-1), superoxide dismutase (SOD), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS). Refs.^23–69)

2.1. EGCG

Various teas, such as green tea (Camellia sinensis, family Theaceae),⁷⁰⁾ black tea (Camellia sinensis (L.) Kuntze var. assamica (J. W. Mast.) Kitam, family Theaceae), and yerba mate (Ilex paraguariensis, Aquifoliaceae), have received attention owing to their health benefits.^71–73) Compared with fermented black tea or semi-fermented yerba mate, green tea is unfermented and has potent antioxidant and anti-inflammatory properties that can alleviate pain and physical dysfunction when used to limit the progression of osteoarthritis.⁷⁴⁾ Green tea contains catechins and numerous phenolic hydroxyl groups.⁷⁵⁾ The four catechin monomers are EGCG, epicatechin, epigallocatechin, and epicatechin gallate. Among them, EGCG may be effective against osteoarthritis.⁷⁶⁾ Although the effect of EGCG in osteoarthritis prevention has been studied at the cellular level, its clinical efficacy remains unclear. In an interleukin-1β (IL-1β) stimulation model, human chondrocytes co-treated with 100 µM EGCG produced significantly less nitric oxide than chondrocytes stimulated with IL-1β alone.²³⁾ The inhibition of nitric oxide production was associated with the suppression of nuclear factor-kappa-B (NF-κB)-dependent expression of the gene encoding inducible nitric oxide synthase (iNOS).²³⁾ Rasheed et al. reported that EGCG inhibits inflammatory responses by modulating microRNA (miRNA) expression; EGCG inhibits the expression of IL-1β-induced disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS)-5 by upregulating the expression of hsa-miR-140-3p.⁷⁷⁾ Furthermore, EGCG suppresses cyclooxygenase (COX)-2 expression/prostaglandin E2 (PGE-2) production by increasing hsa-miR-199a-3p expression.⁷⁸⁾

In addition to being effective at the cellular level, EGCG has been reported to be effective against osteoarthritis in animal studies. Intra-articular injections of EGCG in rats have been shown to be effective in treating osteoarthritis symptoms caused by anterior cruciate ligament tears. In clinical research, habitual tea drinking has been shown to positively correlate with higher bone mineral density (BMD) at multiple skeletal sites.⁷⁹⁾ Tea consumption could be beneficial in the treatment of osteoarthritis.⁸⁰⁾ However, a Mendelian randomized study reported no causal relationship between tea intake and reduced osteoarthritis risk⁸¹⁾; thus, further clinical research is needed.

2.2. Resveratrol

Resveratrol, a natural polyphenolic compound commonly found in grapes, has antioxidant, anti-apoptotic, and anti-inflammatory properties,⁸²⁾ and is effective against age-related diseases such as diabetes and heart disease.^82,83) Studies have reported several mechanisms underlying how resveratrol may ameliorate osteoarthritis-associated symptoms. For example, resveratrol has been shown to inhibit the NF-κB signaling pathway in human osteoarthritic cartilage cells,³³⁾ and inhibit toll-like receptor 4 (TLR4)/NF-κB expression via the TLR4/Ak strain transforming (AKT)/forkhead box O1 (FOXO1) axis in SW1353 cells.³¹⁾ Thus, resveratrol is thought to exert anti-inflammatory effects by suppressing NF-кB activation and decreasing the expression of inflammatory factors.^32,33,46,84) Moreover, resveratrol inhibits TLR4/myeloid differentiation factor 88 (MyD88)-dependent and -independent signaling in human osteoarthritic chondrocytes in vitro, which may slow the progression of osteoarthritis.⁴¹⁾ Resveratrol can also protect chondrocytes from IL-1β-induced damage by activating sirtuin 1 (SIRT1)/FOXO1 signaling.³⁶⁾

Cellular senescence and age-related changes in the extracellular matrix contribute to the development of osteoarthritis.⁸⁵⁾ The SIRT family includes anti-aging proteins whose genetic information is highly conserved among species.⁸⁶⁾ SIRT1 is associated with various aging-related diseases such as obesity, type 2 diabetes, cardiovascular disease, cancer, dementia, arthritis, osteoporosis, and osteoarthritis.⁸⁷⁾ SIRT1 regulates extracellular matrix (ECM) expression and bone homeostasis; promotes mesenchymal stem cell differentiation; plays anti-catabolic, anti-inflammatory, antioxidative, and anti-apoptotic roles; and participates in autophagy processes in osteoarthritis.⁸⁷⁾ SIRT1 expression is reduced in osteoarthritic cartilage.⁸⁸⁾ Resveratrol potently inhibits sterol regulatory element-binding protein-1 (SREBP1) expression by activating the SIRT1/FOXO1 signaling pathway, thereby ameliorating cartilage degradation.³⁵⁾ In the future, the targeting of SIRT1 via bioavailable resveratrol may have potential in the treatment of osteoarthritis.

Regarding the efficacy of orally administered resveratrol, gastric administration of resveratrol (45 mg/kg) to C57BL/6J mice fed a high-fat diet for 12 weeks improved osteoarthritis symptoms and significantly reduced TLR4 expression in knee cartilage cells in vivo.^38,89) The efficacy of resveratrol has been investigated in pilot clinical studies. For example, the oral administration of 500 mg resveratrol/d for 90 d to patients with knee osteoarthritis significantly increased serum aggrecan levels and improved pain and disease activity as measured using the Visual Analogue Scale and Knee Injury and Osteoarthritis Outcome Score, respectively. The activity and functional status of the patients had also improved significantly by day 30, and this effect persisted for 90 d.⁹⁰⁾

2.3. Curcumin

Curcumin is a polyphenolic pigment extracted from the rhizomes of turmeric (Curcuma longa). In vitro and in vivo studies have demonstrated the therapeutic effect of curcumin on osteoarthritis.^51,52) Curcumin promotes collagen synthesis, inhibits inflammatory factor degradation, reestablishes oxidative balance, and inhibits apoptosis in osteoarthritic chondrocytes.⁶⁰⁾ Curcumin suppresses IL-1β-induced chondrocyte apoptosis in vitro by activating autophagy and suppressing the NF-κB signaling pathway.⁶¹⁾ In addition, curcumin exerts chondroprotective effects by activating mitophagy via the AMP-activated protein kinase (AMPK)/phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin pathway.⁵⁷⁾ In a mouse model of post-traumatic osteoarthritis, curcumin alleviated pain symptoms associated with osteoarthritis.⁵²⁾ There have been several reports on the efficacy of curcumin against osteoarthritis in clinical practice.^91,92)

2.4. Ellagic Acid

Ellagic acid, a natural bioactive substance obtained from fruit and nut skin, possesses multiple biological functions, including anti-inflammatory,⁹³⁾ antidiabetic,⁹⁴⁾ and antioxidant activity.⁹⁵⁾ In high glucose-exposed hepatoma G2 (HepG2) cells, ellagic acid alleviated oxidative stress and insulin resistance via the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway.⁹⁶⁾ Ellagic acid exerts protective effects in IL-1β-induced chondrocytes by suppressing IL-1β-induced oxidative stress and NF-κB signaling and upregulating the KEAP1/NRF2 signaling pathway.⁶⁶⁾

The preventive effect of ellagic acid on osteoarthritis has also been demonstrated in a mouse osteoarthritis model established via destabilization of the medial meniscus.⁶⁵⁾ Nonetheless, reports on the clinical use of ellagic acid in osteoarthritis remain scarce, warranting further research.

2.5. Carnosic Acid

Rosemary (Salvia rosmarinus) is an evergreen shrub native to the Mediterranean region.

Carnosic acid, the most abundant polyphenolic constituent of rosemary, has various biological regulatory functions and can activate oxidative stress defense systems (KEAP1/NRF2 signaling pathway) in vivo.⁹⁷⁾ Satoh et al. demonstrated that carnosic acid reduces ischemia-induced brain damage via this pathway in an in vivo mouse model of cerebral ischemia.⁹⁷⁾ Carnosic acid has also been reported to enhance NGF production in T98G human glioblastoma cells⁹⁸⁾ and can protect neurons from oxidative stress.⁹⁹⁾ Enzymes such as superoxide dismutase (SOD)-II, catalase, and heme oxygenase-1 (HO-1) are induced by NRF2 activation and subsequently remove reactive oxygen species (ROS) in vivo. ROS oxidize lipids, proteins, and DNA, causing cellular dysfunction and damage. Insufficient processing of ROS generated in the body leads to oxidative stress, which contributes to cancer, lifestyle-related diseases, and dementia.^100,101) Oxidative stress in osteoarthritis is associated with cellular senescence and the expression of catabolic factors such as inflammatory cytokines and ECM-degrading proteases.¹⁰²⁾ Consistent with the concept that age-related oxidative stress alters cell signaling, studies have demonstrated that age-related disruptions in insulin-like growth factor 1 (IGF-1) signaling in human chondrocytes result in decreased ECM and protein synthesis.^103,104) At optimal treatment levels of 10–50 µmol/L, carnosic acid induces the expression of HO-1 and miR-140 and suppresses cartilage degeneration in human chondrocytes.⁶⁹⁾ Furthermore, HO-1 levels may be restored under IL-1β treatment, which specifically inhibits the enzyme’s antioxidant effect. The mechanism by which this natural compound acts depends on the downregulation of matrix metalloproteinase (MMP)-13 and ADAMTS-5, activation of NRF2, and regulation of KEAP1 expression. In addition, the KEAP1/NRF2 transcriptional pathway and increased miR-140 expression, which binds to the 3′-untranslated region of basic leucine zipper transcription factor 1 (BACH1) (HO-1 repressor), may be involved in this process.⁶⁹⁾ Studies on the effect of carnosic acid on osteoarthritis remain limited; therefore, further studies at the biological and clinical levels are warranted.

3. OSTEOPOROSIS

Osteoporosis is a common chronic disease that mostly affects older adults, with women accounting for two-thirds of all cases.¹⁰⁵⁾ The risk of osteoporosis development increases markedly during the postmenopausal period.¹⁰⁶⁾ Global epidemiological studies have suggested that over 200 million individuals suffer from vertebral fractures due to osteoporosis.¹⁰⁷⁾ The pathogenic mechanisms of osteoporosis can be divided into those that decrease bone mass and those that decrease bone quality.¹⁰⁸⁾ Mechanisms that decrease bone mass include decreased bone formation, increased bone resorption, and disrupted bone formation-resorption coupling. Examples of mechanisms that decrease bone quality include the degradation of non-calcified components (i.e., collagen) in bone and abnormal microstructure of calcified components. Several drug classes (such as bisphosphonates, calcitonin, and selective estrogen receptor modulators) can effectively restore bone strength and reduce bone strain in the treatment of osteoporosis.¹⁰⁹⁾ However, some of these therapeutics are expensive, associated with serious adverse effects, and may require long-term use.¹⁰⁹⁾ Studies have shown that natural products derived from foods and plants have great potential to prevent and treat osteoporosis, via various mechanisms of action. Recent studies have shown that the consumption of antioxidant-rich fruits and vegetables correlates with a lower risk of osteoporosis development and reduced BMD in postmenopausal women.¹¹⁰⁾ Oxidative stress promotes bone remodeling and loss, whereas antioxidants reduce oxidative stress and prevent bone loss.¹¹¹⁾ Thus, natural, food-derived remedies may be an adjunctive or alternative treatment for osteoporosis. In this section, we discuss the preventive effects and mechanisms of action of several functional ingredients against osteoporosis. A schematic of the prevention of osteoporosis using functional ingredients is shown in Fig. 3. In this chapter, we summarize the effects of these five components on the prevention of osteoporosis, focusing on TRAF6-dependent mechanisms.

Fig. 3. Mechanism of Action of Functional Ingredients in the Prevention of Osteoporosis

A: epigallocatechin gallate (EGCG); B: resveratrol; C: curcumin; D: ellagic acid; E: carnosic acid. Blue indicates inhibition. Red arrows indicate upregulation. Nuclear factor erythroid 2-related factor 2 (NRF2), receptor activator of nuclear factor kappa-B ligand (RANKL), receptor activator of nuclear factor-kappa-Β (RANK), osteoprotegerin (OPG), TNF receptor associated factor 6 (TRAF6), microRNA (miR), nuclear factor-kappa-B (NF-κB), nuclear factor of activated T cells 1 (NFATc1), extracellular signal regulated kinase (ERK), interleukin (IL), tumor necrosis factor (TNF), bone morphogenetic proteins (BMP), sirtuin (SIRT), and nuclear forkhead box O1 (Nu-FOXO1). Refs.^112–143)

3.1. EGCG

EGCG, one of the most abundant bioactive catechins found in green tea, promotes bone formation both in vitro and in vivo,^118,144,145) suppresses the activity of the Hippo/Yes-associated protein 1 (YAP) pathway by upregulating the long non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1), and potentiates tumor necrosis factor-alpha (TNF-α)-induced inhibition of osteoblast differentiation.¹¹⁵⁾ Chen et al. reported that EGCG, at effective concentrations ranging from 1 to 10 µmol/L, can inhibit osteoclastogenesis in co-cultures of RAW264.7 and ST2 cells by modulating the receptor activator of NF-κB (RANK)/receptor activator of the NF-κB ligand (RANKL)/osteoprotegerin (OPG) pathway.¹¹⁴⁾ Previous studies have investigated the association between EGCG and the alleviation of osteoporosis symptoms. EGCG has been found to markedly induce cyclin D1, β-catenin, and Wnt protein expression while suppressing the expression of peroxisome proliferator-activated receptor γ protein in a mouse model of secondary osteoporosis.¹⁴⁶⁾ Moreover, ingestion of EGCG contributes to fracture healing and promotes bone morphogenetic protein 2 (BMP-2) expression.¹¹⁷⁾ A single cup of green tea has been found to yield circulating blood levels of 1 µmol/L EGCG,^117,147) and an oral dose of 1600 mg EGCG has been reported to yield plasma levels of 7.6 µmol/L EGCG under fasting conditions.^117,148) In addition, several clinical studies have reported an association between green tea consumption and bone health, including lower hip fracture rates and higher BMD in habitual tea drinkers.¹⁴⁹⁾ Thus, prevention of osteoporosis may be achieved by the daily consumption of EGCG-containing green tea.

3.2. Resveratrol

Resveratrol has potent bone-protective properties.^122,150,151) There has been evidence that resveratrol contributes to increased bone mass and that it has antioxidant, anti-inflammatory, and estrogenic properties. Resveratrol increased survival and promoted the maturation of osteoblastic MC3T3-E1 cells responsible for new bone formation in vitro.¹²⁹⁾ In addition, resveratrol promoted the proliferation and differentiation of hydrogen peroxide (H₂O₂)-treated osteoblasts, while inhibiting apoptosis. During this process, SIRT1 expression is upregulated, and the expression of nuclear Nu-FOXO1, a highly transcriptionally active regulator of redox balance, is significantly increased.¹³⁰⁾

Resveratrol increases the levels of miR-92b-3p, suppresses the activity of the nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)/NF-κB signaling pathway, increases the activity of the BMP-2/Smad/Runx2 signaling pathway, suppresses the proliferation of osteoclasts, stimulates the proliferation of bone marrow stromal cells and the differentiation of osteoblasts, and improves estrogen deficiency-induced osteoporosis.¹²⁴⁾ Resveratrol improved bone loss and promoted bone formation by enhancing oxidative stress tolerance in ovariectomized rat, has been found to restore the RANKL/OPG ratio, slightly increase BMD, and moderately decrease the expression levels of IL-23, IL-17A, IL-1β, and TNF-α.¹²⁵⁾ Notably, experimental results have suggested that the transcriptional upregulation of FOXO1 may prevent osteoporosis.¹³¹⁾

In an ovariectomized rat model of postmenopausal osteoporosis, resveratrol supplementation reduced estrogen deficiency-induced bone loss and deterioration of the bone beam structure.¹³²⁾ In a randomized placebo-controlled trial, low-dose resveratrol supplementation significantly improved BMD in the lumbar spine and femoral neck, while reducing the expression of the bone resorption marker C-terminal telopeptide in postmenopausal women.¹⁵²⁾

3.3. Curcumin

Curcumin has antioxidant properties and modulates bone metabolism.^153–155) Curcumin inhibits osteoclastogenesis in RAW264.7 cells by suppressing NF-κB signaling.¹³⁴⁾ Curcumin has been shown to promote bone formation and regeneration by reducing the apoptosis of H₂O₂-stimulated osteoblasts¹³³⁾ and improving mitochondrial function in osteoblasts.¹³⁸⁾ Curcumin ameliorates the oxidative stress-induced apoptosis of osteoblasts by maintaining mitochondrial function and activating Akt/glycogen synthase kinase-3 beta (GSK-3β) signaling. In addition, curcumin is used in the prevention and treatment of chronic metabolic diseases, including osteoporosis, owing to its ability to neutralize free radicals.¹⁵⁶⁾ In a rat ovariectomized osteoporosis model, curcumin exerted a preventive effect on osteoporosis by regulating the enhancer of the zeste homolog 2 (EZH2)/Wnt/β-catenin pathway.¹⁵⁷⁾ In addition, in a randomized, double-blind pilot study, curcumin modulated bone metabolism markers and increased bone mineral density in postmenopausal women with osteoporosis.¹⁵⁸⁾

3.4. Ellagic Acid

Epidemiological studies have suggested that the incidence of cardiovascular disease and postmenopausal osteoporosis is lower in the Mediterranean region, which has been partially attributed to herb- and nut-rich diets.¹⁵⁹⁾ Ellagic acid extracted from walnuts is believed to prevent osteoporosis. Papoutsi et al. found that ellagic acid from walnut extract significantly reduced the TNF-α-induced endothelial expression of both vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1).¹⁶⁰⁾ Ellagic acid reduces osteoclastogenesis by suppressing the p38 signaling pathway downstream of RANKL and inhibiting bone resorption and actin ring formation.¹⁴⁰⁾

Ellagic acid inhibits RANKL-induced osteoclastogenesis by inhibiting the RANK signaling pathway in RAW264.7 mouse macrophages.¹⁴¹⁾ In addition, ellagic acid alleviated osteoporosis-related symptoms in hindlimb unloaded and ovariectomized mouse models.¹⁶¹⁾ However, investigations on the efficacy of ellagic acid in osteoporosis in humans have not yet been performed.

3.5. Carnosic Acid

There are limited reports on the preventive effects of carnosic acid against osteoporosis. Thummuri et al. reported that carnosic acid inhibits RANKL-induced osteoclastogenesis and oxidative stress by upregulating NRF2 transcriptional targets.¹⁴²⁾ Zheng et al. demonstrated that carnosic acid attenuates ovariectomy-induced bone loss in a mouse model.¹⁴³⁾ Elbahnasawy et al. demonstrated that rosemary effectively reduced calcium deficiency-related bone loss and prevented bone resorption and osteoporosis in rats.¹⁶²⁾ As there have been no clinical studies, further research on the preventive effects of carnosic acid on osteoporosis in humans should be conducted.

4. RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation, synovial hyperplasia with increased cell density, and inflammatory cell infiltration, leading to pannus formation and irreversible cartilage and bone destruction.¹⁶³⁾ It affects approximately 0.5–1% of the global population.¹⁶⁴⁾ The pathobiology of rheumatoid arthritis is multifaceted and involves complex interactions among T cells, B cells, and various pro-inflammatory cytokines, including TNF-α and IL-6.¹⁶⁵⁾ Nonsteroidal anti-inflammatory drugs, such as celecoxib, diclofenac, and ibuprofen; disease-modifying anti-rheumatic drugs, such as azathioprine, methotrexate, and cyclosporine; biological agents, such as anakinra, infliximab, and rituximab; and immune suppressants are used to relieve symptoms related to rheumatoid arthritis.¹⁶⁶⁾ However, these drugs often have serious adverse effects, including gastric ulcers, hypertension, hepatotoxicity, and renal abnormalities, which limit their use in many cases. Thus, there is an urgent need for the development of novel therapeutic agents against rheumatoid arthritis. Accumulating evidence suggests that food- and herb-derived components may relive symptoms of rheumatoid arthritis via anti-apoptotic, antioxidant, anti-inflammatory, and immunosuppressive effects, and by modulating TNF-α and IL-6 secretion. For example, both laboratory and clinical studies have shown that dietary n-3 polyunsaturated fatty acids can reduce pain associated with conditions such as rheumatoid arthritis.¹⁶⁷⁾ In addition, EGCG is expected to be developed as a novel functional component with a safer adverse effects profile than existing drugs, with potential as an IL-6 inhibitor.¹⁶⁸⁾ In this section, we describe the effects of several functional ingredients on rheumatoid arthritis symptoms. A schematic of the prevention of rheumatoid arthritis using functional ingredients is shown in Fig. 4. This chapter summarizes the effects of the five components on rheumatoid arthritis, with a focus on mitogen-activated protein kinase (MAPK) and NF-κB pathways.

Fig. 4. Mechanisms of Action of Five Functional Ingredients in the Relief of Rheumatoid Arthritis-Associated Symptoms

A: epigallocatechin gallate (EGCG); B: resveratrol; C: curcumin; D: ellagic acid; E: carnosic acid. Blue indicates inhibition. p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa-B (NF-κB), hypoxia-inducible factor (HIF), tumor necrosis factor (TNF), interleukin (IL), poly (ADP-ribose) polymerase (PARP), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), signal transducer and activator of transcription (STAT). Refs.^169–201)

4.1. EGCG

Over the past two decades, extensive studies have validated the chondroprotective effects of EGCG. Singh et al. reported that EGCG selectively inhibits the p46 isoform of IL-1β-induced c-Jun-N-terminal kinase.²⁰²⁾ EGCG pretreatment significantly inhibits the expression and activity of MMP-1 and MMP-13 in cultured human osteoarthritis chondrocytes in a dose-dependent manner.²⁰³⁾ In addition, EGCG has been shown to protect chondrocytes in vitro. MMPs are enzymes capable of degrading various ECM components and play key roles in cartilage destruction in arthritic joints and tissue remodeling.²⁰⁴⁾

In animals, EGCG exhibits anti-arthritic effects by modulating the expression of NRF2 and HO-1.²⁰⁵⁾ Furthermore, in vivo experiments have demonstrated that EGCG slows cartilage destruction in rats with rheumatoid arthritis.¹⁷²⁾ The efficacy of EGCG or green tea extract in human rheumatoid arthritis or osteoarthritis has not yet been tested in phase-controlled trials.²⁰⁶⁾ Therefore, current data is insufficient to validate or reject the potential benefits of EGCG in patients with rheumatoid arthritis.

4.2. Resveratrol

Resveratrol inhibits NF-κB activation and downregulates the expression of inflammatory genes such as COX-2, IL-1β, and IL-6, which play important roles in various forms of arthritis.¹⁷⁷⁾ Furthermore, the anti-apoptotic and anti-inflammatory properties of resveratrol via NF-κB inhibition have been reported in chondrocytes.¹⁷⁹⁾ Resveratrol also inhibits synovial cell hyperplasia, which plays a crucial role in the pathogenesis of rheumatoid arthritis, by allowing the release of cytochrome c from mitochondria to the cytosol in a SIRT1-dependent manner.²⁰⁷⁾ The therapeutic effects of resveratrol on collagen-induced arthritis have also been investigated; the prophylactic or therapeutic administration of resveratrol reduces clinical parameters and bone erosion by inhibiting Th17 and B cell function.¹⁸⁶⁾ Resveratrol also inhibits COX-1 and COX-2, vital enzymes in the pathogenesis of rheumatoid arthritis.²⁰⁸⁾ Resveratrol has been shown to reduce the expression levels of COX-2 and PGE-2 in rat models.¹⁸³⁾ A systematic review and meta-analysis on the pharmacological efficacy of resveratrol in preclinical models of rheumatoid arthritis also reported that resveratrol reduces arthritis and joint index scores.²⁰⁹⁾

In clinical studies, resveratrol has been shown to exert therapeutic effects against various autoimmune diseases, including rheumatoid arthritis. Clinical research is also ongoing, with randomized controlled clinical trials reporting improved disease activity, biochemical, and clinical scores in patients treated with resveratrol.²¹⁰⁾ Resveratrol can alleviate rheumatoid arthritis by preventing inflammation and oxidation, inhibiting cell proliferation, promoting synovial tissue apoptosis, and inhibiting angiogenesis. Therefore, resveratrol has potential as a novel therapeutic agent for the treatment of rheumatoid arthritis.

4.3. Curcumin

Curcumin has anti-inflammatory effects, and modulation of NF-κB^211,212) and TNF-α^213,214) signaling is involved in its mechanisms of action. Curcumin affects a variety of immune cells, including macrophages, dendritic cells, B cells, and T cells.¹⁸⁸⁾ Moreover, curcumin has been shown to block the production of TNF-α and its downstream inflammatory mediators. Both NF-κB and TNF-α are associated with rheumatoid arthritis, and their inhibitors are used as effective therapeutic agents for rheumatoid arthritis. Curcumin has been reported to exert preventative effects in a rat model of collagen-induced arthritis in vivo.¹⁸⁷⁾ At the clinical level, randomized controlled trials have shown that curcumin exerts superior clinical efficacy in the treatment of rheumatoid arthritis.²¹⁵⁾ As such, the preventive effect of curcumin on rheumatoid arthritis has attracted considerable attention.

4.4. Ellagic Acid

Ellagic acid exerts its anti-inflammatory effects by modulating NF-κB activity and inhibiting the IL-1β-induced nuclear migration of p65 and p50.²¹⁶⁾ Ellagic acid decreases IL-13 and TNF-α production in stimulated human peripheral blood mononuclear cells.²¹⁷⁾ Ellagic acid has been reported to suppress inflammation in various organs and significantly downregulates the mRNA expression of IL-6 and TNF-α.²¹⁸⁾ Allam et al. found that ellagic acid reduced adjuvant-induced arthritis-related pathology in a mouse model by downregulating pro-inflammatory cytokines and upregulating anti-inflammatory cytokines.¹⁹⁹⁾ Fikry et al. found that ellagic acid was as effective as celecoxib in treating adjuvant-induced arthritis in rats.¹⁹⁸⁾ In addition, ellagic acid has been shown to reduce the severity of rheumatoid arthritis in rats with collagen-induced arthritis by inhibiting cell proliferation, inflammation, and oxidative stress; promoting the apoptosis of MH7A cells; downregulating the metastasis associated-1 (MTA-1)/histone deacetylase-1 (HDAC-1) complex; and promoting the expression of transcription factor Nur77 via HDAC1 deacetylation.¹⁹⁷⁾ However, no clinical studies on the effect of ellagic acid on rheumatoid arthritis have been reported; therefore, further investigation is needed.

4.5. Carnosic Acid

Carnosic acid inhibits osteoclastogenesis and bone resorption in vitro, and its therapeutic effect in preventing joint destruction has been demonstrated in a CIA Wistar rat model.²⁰⁰⁾ Carnosic acid has been shown to inactivate p38 MAPK, which is induced by RANKL and macrophage colony-stimulating factor. It also inhibits NF-κB phosphorylation, leading to the downregulation of pro-inflammatory cytokines.²⁰¹⁾ Carnosic acid also ameliorates osteoclastogenesis and bone loss in collagen-induced arthritic db/db mice by modulating the ROS-dependent p38 pathway, which suppresses inflammation.²⁰¹⁾ However, further clinical studies on the effect of carnosic acid on rheumatoid arthritis are needed.

5. CONCLUSION

In this review, we summarized the available literature on the therapeutic effects of five functional ingredients against osteoarthritis, osteoporosis, and rheumatoid arthritis. Overall, we concluded that these conditions share similar underlying mechanisms and that functional ingredients can exert preventive and therapeutic effects on locomotive syndrome through antioxidant, anti-inflammatory, and immune-modulating activity. However, data on specific dietary recommendations for patients are limited. In addition to future large-scale clinical trials, additional studies on the underlying mechanisms of these diseases and the pharmacological effects of these functional ingredients may help to accurately define and validate their therapeutic use. In addition, other functional ingredients not discussed here have been shown to improve the symptoms of musculoskeletal disorders in different systems. For example, Lactobacillus rhamnosus GG improves osteoporosis by affecting the gut microbiota in addition to the Th17/Treg balance.²¹⁹⁾ Functional food ingredients can be expected to have various effects. We are currently investigating the effects of both food- and plant-derived ingredients on the suppression of disease progression via suppression of integrin expression. Through such research, it will be possible to clarify the effects of natural product-derived ingredients, which have fewer side effects than antibody drugs, on the prevention of musculoskeletal diseases. Additional research and clinical trials will help to facilitate the use of natural medicines (including dietary and herbal medicines) either alone or as adjuncts to current therapies for musculoskeletal disorders.

Acknowledgments

The authors would like to thank Dr. Kengo Banshoya for creating the chemical structure plots shown in Fig. 1.

Funding

This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number: 21K17672 (S.S.), Tojuro Iijima Foundation for Food Science and Technology (S.S.), Public Foundation of Elizabeth Arnold-Fuji (S.S.), Koyanagi Foundation (S.S.), and Kanamori Foundation (S.S.).

Author Contributions

Conceptualization; S.S. methodology; S.S. and S.K. validation; S.S. formal analysis; S.S. investigation; S.S. resources; S.S. data curation; S.S. writing—original draft preparation; S.S. writing—review and editing; S.S. and S.K. visualization; S.S. supervision; S.S. and S.K. project administration; S.S. funding acquisition. All authors have read and agreed to the published version of the manuscript.

Conflict of Interest

The authors declare no conflict of interest.

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